A strategy toward the total synthesis of durhamycin A, an aureolic acid natural product possessing potent anti-HIV properties, is described. The proposed synthesis utilizes a convergent approach to assemble the highly functionalized tricyclic aglycone, a conserved structural motif among the aureolic acids. The key steps include the [4 + 2] annulation to construct the substituted naphthalene core and the asymmetric allylation to install the polyketide side chain. The proposed synthetic route is highly amenable to analog synthesis, as it would allow late-stage installation of preassembled side chains onto a common central scaffold. Validation of this strategy would enable access to a wide range of aureolic acid analogs, potentially leading to the discovery of novel antibiotic and anti-HIV agents. PUBLIC HEALTH RELEVANCE: The proposed study on the synthesis of durhamycin A will enable access to a wide range of synthetic analogs, which will significantly enhance the discovery efforts on novel antibiotic and anti-HIV agents.